Nitric oxide generator and non-deliquescent tablet for use in same

ABSTRACT

A method to generate nitric oxide is disclosed in one embodiment in accordance with the invention. A tablet may be placed within a vessel such that it is in thermal communication with a heat source to receive heat therefrom. The tablet is then heated to melt at least one reactant forming the tablet. The tablet may contain reactants that are substantially non-deliquescent and form nitric oxide in response to heat from the heat source.

RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 10/733,805, filed on Dec. 10, 2003, now patented as U.S. Pat.No. 7,220,393, which claims the benefit of Canada Patent Application No.2413834 filed on Dec. 10, 2002.

BACKGROUND

1. The Field of the Invention

This invention relates to nitric oxide therapy and more particularly toapparatus and methods for generating and delivering nitric oxide.

2. Background

Although it is one of the simplest biological molecules in nature,nitric oxide plays a significant role in nearly every phase of biologyand medicine. From its role as a critical endogenous regulator of bloodflow and thrombosis, to a principal neurotransmitter mediating erectilefunction, to a major pathophysiological mediator of inflammation andhost defense, there are few pathological conditions where nitric oxidedoes not play a significant role. Discoveries relating to nitric oxidehave prompted vigorous research in a variety of fields includingchemistry, molecular biology, and gene therapy. In just the last twodecades, tens of thousands of scientific papers addressing variousaspects of this molecule have been published, most of these within thelast decade.

One method for delivering nitric oxide to the body is by inhalingtherapeutic doses (e.g., 20 to 100 ppm) of nitric oxide gas. Thisdelivery method has been introduced and studied over the last decade totreat conditions such as pulmonary hypertension, hypoxemia, respiratorydistress syndrome in newborns, and sickle cell disease. Providing nitricoxide in the respiratory gas dilates pulmonary vessels by relaxingvascular smooth muscle cells. This decreases pulmonary vascularresistance and redistributes pulmonary blood flow to reduce pulmonaryarterial pressure and improve arterial oxygenation.

Currently, various methods have been disclosed for generating nitricoxide, including production with polymers or electrochemical productionwith aqueous solutions of nitric oxide precursors. One method forproducing nitric oxide was disclosed in 1956 in a paper titled “A NewMethod of Preparing Nitric Oxide” authored by James D. Ray and RichardA. Ogg Jr. In that paper, the authors disclosed a method for generatingnitric oxide that involves heating a dry powdered mixture of potassiumnitrite, potassium nitrate, chromic oxide, and ferric oxide with ayellow flame. The powder was optionally mixed with water to form a stiffpaste which could be molded and dried to form cylindrical shapes orpellets. The resulting nitric oxide gas was very pure, in some cases asmuch as 99.78 percent pure.

Nevertheless, the composition disclosed by Ray and Ogg is not suitableto produce a stable, long-lasting tablet for generating nitric oxide. Inparticular, the potassium nitrite is deliquescent, tending to absorbexcessive amounts of water from the atmosphere causing the material toliquefy. Other ingredients, such as the ferric oxide, are not readilycompressed to form a tablet with acceptable friability and hardness.

In view of the foregoing, what is needed is a method and apparatus toproduce a stable, long-lasting tablet that will release nitric oxide insuitable quantities, predictably, over a suitable time upon beingheated. Further needed is an apparatus for heating and capturing nitricoxide generated by such a tablet. Further needed is an apparatus fordiluting the nitric oxide to a therapeutically safe level. Yet furtherneeded is a tablet having acceptable hardness and friability that can bemanufactured in large quantities by mass production, distributed,stored, and easily used. Further needed is a tablet that will producenitric oxide with acceptable efficiency. Yet further needed are methods,materials, and techniques to improve upon the method and compositiondisclosed by Ray and Ogg.

BRIEF SUMMARY OF THE EMBODIMENTS

Consistent with the foregoing, and in accordance with the invention asembodied and broadly described herein, an apparatus to generate nitricoxide is disclosed in one embodiment in accordance with the invention asincluding a heat source and a vessel containing the heat source. Atablet may be placed within the vessel such that it is in thermalcommunication with the heat source to receive heat therefrom. The tabletmay contain reactants that are substantially non-deliquescent and formnitric oxide in response to heat from the heat source.

In selected embodiments, the tablet further comprises an inert binderproviding a substantially solid path of thermal conduction betweengranules of reactants. The tablet may be compressed to a hardnessproviding a thermal conductivity effective to heat the reactantsinternal thereto substantially exclusively by thermal conduction. Incertain embodiments, the hardness of the tablet is selected to begreater than 5 kiloponds. In other embodiments, the hardness of thetablet is selected to be greater than 9 kiloponds. In yet otherembodiments, the hardness of the tablet is selected to be from about 10kiloponds to about 20 kiloponds.

In certain embodiments, the heat source is controlled to melt, yet avoidvaporizing, one or more of the reactants. In other embodiments, the heatsource is controlled to melt one or more of the reactants, and to avoidvaporizing any of the reactants.

In certain embodiments, the reactants consist substantially of anon-deliquescent nitrite compound, a nitrate compound, and a singlemetal oxide. In selected embodiments, the inert binder may includecalcium silicate. In other embodiments, the non-deliquescent nitritecompound may include sodium nitrite. Similarly, the nitrate compound mayinclude potassium nitrate and the metal oxide may include chromic oxide.

In a second aspect of the invention, a stable nitric-oxide-producingtablet may include substantially non-deliquescent reactants formingnitric oxide in response to heat applied thereto. These reactants mayinclude a non-deliquescent nitrite compound, a nitrate compound, and ametal oxide. The tablet may also include an inert binder providing asubstantially solid path of thermal conduction between the reactants.

In selected embodiments, the inert binder may include calcium silicate.In other embodiments, the non-deliquescent nitrite compound may includesodium nitrite. Similarly, the nitrate compound may include potassiumnitrate and the metal oxide may include chromic oxide.

In a third aspect of the invention, a method of generating nitric oxidemay include providing a solid tablet comprising non-deliquescentreactants. This tablet may then be heated to melt at least one of thereactants to promote reaction thereof, thereby generating nitric oxide.The nitric oxide may then be mixed with a diluent gas to provide atherapeutically safe and effective concentration of nitric oxide.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other objects and features of the present inventionwill become more fully apparent from the following description andappended claims, taken in conjunction with the accompanying drawings.Understanding that these drawings depict only typical embodiments inaccordance with the invention and are, therefore, not to be consideredlimiting of its scope, the invention will be described with additionalspecificity and detail through use of the accompanying drawings inwhich:

FIG. 1 is a high-level block diagram of one embodiment of a nitric oxidegenerator in accordance with the invention;

FIG. 2A is a front perspective view of one embodiment of animplementation of a nitric oxide generator in accordance with theinvention;

FIG. 2B is a rear perspective view of the nitric oxide generatorillustrated in FIG. 2A;

FIG. 3 is an exploded perspective view of the nitric oxide generatorillustrated in FIGS. 2A and 2B;

FIG. 4 is a flow chart of one embodiment of a method for generatingnitric oxide;

FIG. 5A is a high-level block diagram of one embodiment of a feedbacksystem for use with a nitric oxide generator in accordance with theinvention;

FIG. 5B is a high-level block diagram of another embodiment of afeedback system for use with a nitric oxide generator in accordance withthe invention;

FIG. 6 is a flow chart of one embodiment of a method for creating anon-deliquescent nitric-oxide-producing tablet in accordance with theinvention;

FIG. 7 is an enlarged perspective view of one embodiment of a tablet inaccordance with the invention, showing the tablet's granular structure;and

FIG. 8 is a graph showing nitric oxide production of a tablet as afunction of time and compression force.

DETAILED DESCRIPTION OF THE EMBODIMENTS

It will be readily understood that the components of the presentinvention, as generally described and illustrated in the Figures herein,could be arranged and designed in a wide variety of differentconfigurations. Thus, the following more detailed description of theembodiments of apparatus and methods in accordance with the presentinvention, as represented in the Figures, is not intended to limit thescope of the invention, as claimed, but is merely representative ofcertain examples of presently contemplated embodiments in accordancewith the invention. The presently described embodiments will be bestunderstood by reference to the drawings, wherein like parts aredesignated by like numerals throughout.

Referring to FIG. 1, in general, a nitric oxide generator 10 inaccordance with the invention may include a vessel 12 and a heat source14 within the vessel 12. The heat source 14 may be in thermalcommunication with a tablet 16. The tablet 16 may contain reactants thatgenerate nitric oxide gas when heated. The reactants in the tablet 16may be depleted after heating the tablet 16 for a given time andtemperature, after which the tablet 16 may be replaced. In selectedembodiments, the tablet 16 may retain its shape and structure after thereactants have been substantially depleted.

The heat source 14 may be in direct contact with the tablet 16 toconduct heat directly to the tablet 16. Alternatively, the heat source14 may radiate heat, which may then be absorbed by the tablet 16 withoutphysical contact. In either case, the heat source 14 may be placedinside the vessel 12 in order to efficiently transfer heat to the tablet16. This may also provide a degree of safety when handling or cominginto contact with the generator 10.

In selected embodiments, the nitric oxide generator 10 may also includean inlet 18 to allow diluent gases to enter the vessel 12 and therebymix with and dilute the nitric oxide gas. The resulting diluted nitricoxide gas may then exit the vessel 12 through an outlet 20 where it maybe stored or conveyed to a person or animal to provide therapy.

Referring to FIGS. 2A and 2B, one specific and non-limitingimplementation of a nitric oxide generator 10 in accordance with theinvention is illustrated. As shown, in one embodiment a nitric oxidegenerator 10 may include a body portion 22 which may support a vessel12. In this embodiment, the vessel 12 is provided in the form of a clamshell which may include separable upper and lower portions. Theseportions may be separated to provide access to the heat source 14 andallow tablets 16 to be inserted or replaced. In selected embodiments, athumbscrew 24 or clamp 24 may be used to keep the upper and lowerportions of the clam shell together to seal the vessel 12 and preventinjury. As will be shown in FIG. 3, the clam shell may also include oneor more inlets 18 and outlets 20 to allow diluent gases to enter thevessel 12, mix with nitric oxide gas, and exit the vessel 12. Theseinlets 18 and outlets 20 may, in certain embodiments, be fitted with alatch, coupling, fitting, or other connector to connect to a hose orother device.

In selected embodiments, a generator 10 may also include a control panel26 to adjust various operational parameters of the nitric oxidegenerator 10. For example, the control panel 26 may be used to adjustthe temperature, current, or heat output of the heat source 14 which mayin turn adjust the amount of nitric oxide produced. This may be used toadjust the concentration of nitric oxide in gases exiting the vessel 12.In other embodiments, the control panel 26 may be used to regulate theflow of diluent gases through the vessel 12 with a valve or othercontrol device. This may also adjust the concentration of nitric oxidein gases exiting the vessel 12. In other embodiments, the control panel26 may be used to turn the generator 10 on or off, set a timer to turnthe generator 10 on or off, set a temperature, current, or heat profilefor the heat source 14 that changes (e.g. monotonically orprogrammatically) over time 14, or the like. Similarly, the controlpanel 26 may be configured to trigger one or more alarms when the nitricoxide concentration rises above or falls below a selected threshold.These examples represent just a few possible functions for a controlpanel 26.

The generator 10 may also include a power supply panel 28 connecting toa power cord or other source of electricity. A switch 30 may be providedto selectively connect or interrupt the supply of power to the generator10.

Referring to FIG. 3, an exploded view of the generator 10 of FIGS. 2Aand 2B is illustrated. As shown, the generator 10 may include a bodyportion 22, a control panel 26, and power supply panel 28, which may beinserted into the body portion 22. A cover plate 30 may be used toprovide access to the control panel 26, power supply 28, and possibly aheating element 36 from below the generator 10. A vessel 12, in thisexample a selectively opened and closed clam shell 12 a, 12 b, may beinserted into or mounted to the body portion 22. A lower portion 12 a ofthe vessel 12 may be attached to the body portion 22 using a mountingplate 32, washer 34, and one or more fasteners, such as screws, rivets,welds, or the like. The lower portion 12 a may include one or severalports, such as an inlet 18 and outlet 20, to allow diluent gases to passthrough the vessel 12.

In selected embodiments, a heating element 36, such as a calrod 36 orcartridge heater 36, may be inserted through the mounting plate 32 andwasher 34 where it may be connected to a power source outside the vessel12 a, 12 b. One or more tablets 16, having apertures therein, may beplaced over the heating element 36. The tablets 16 may be stackeddirectly on top of one another or may be separated by a washer or otherspacer. The tablets 16 may be heated through direct contact with theheating element 36 or may, alternatively, absorb heat radiated from theheating element 36. The temperature of the heating element 36 may becontrolled to provide a regulated amount of heat (e.g., between 200° C.and 700° C.) to the tablets 16. This enables nitric oxide to begenerated over a period of time and in a controlled manner.

In selected embodiments, the tablets 16 may be surrounded by aperforated baffle 38. The baffle 38 may regulate heat dissipation fromthe tablets 16, provide more uniform heating of the tablets 16, regulatethe flow of diluent gases over the tablets 16, or the like. The baffle38, by contrast, may allow nitric oxide gas to pass through slots orapertures in the baffle 38 to mix with diluent gases passing through thevessel 12.

An upper portion 12 b of the vessel may be used to cover the heatingelement 36 and tablets 16, seal the vessel 12, prevent the escape ofnitric oxide, and retain heat within the vessel 12. The upper portion 12b may be retained over the lower portion 12 a by, for example, athumbscrew 24, clamp 24, or other suitable retention mechanism.

Referring to FIG. 4, in selected embodiments, a method 50 for generatingnitric oxide may include providing 52 one or more tablets 16 containingnon-deliquescent reactants for producing nitric oxide. Use ofnon-deliquescent reactants enables manufacture of an environmentallystable tablet 16 that will retain its ability to produce nitric oxideover time. As will be explained in more detail hereafter, the stabilityof the reactants enable production of a tablet 16 that is both harderand less friable than may be possible with deliquescent reactants.Additional hardness, which may be a function of the amount ofcompressive force applied to the tablet 16, may increase the nitricoxide production of the tablet 16 by improving the solidity and thusthermal conductivity of the tablet 16. As will be explained in moredetail hereafter, this provides a tablet 16 having improved stabilityand an improved ability to produce nitric oxide, and to do so morepredictably, compared to a tablet 16 containing one or more deliquescentreactants, such as potassium nitrite.

Once a tablet 16 is provided 52, the method may include heating 54 thetablet 16 to melt one or more reactants. This may cause the meltedreactants to come into intimate molecular contact, and even to migratethrough the tablet until they come into contact with other reactants,thereby initiating the nitric-oxide producing reaction. This alsoenables certain ones of the reactants to be reacted as liquids (orvapors, or both) with heat of a fairly modest temperature (e.g.,300-500° C.). In certain embodiments, reactants may be vaporized toreact in a vapor phase. In selected embodiments, the substantiallynon-deliquescent reactants may include sodium nitrite, potassiumnitrate, and chromium oxide. These reactants may produce nitric oxide inaccordance with the following stoichiometric equation:3NaNO₂+KNO₃+Cr₂O₃→2KNaCrO₄+4NO(g)

Of the above reactants, sodium nitrite (NaNO₂) has the lowest meltingtemperature (270° C.). Thus, upon heating the reactants to 270° C., thesodium nitrite may begin to melt and intermingle with molecules of otherreactants. It may even flow through the tablet 16 to make intimatecontact with other reactants, thereby initiating thenitric-oxide-producing reaction. In selected embodiments, thetemperature may be controlled to avoid vaporizing any of the reactants.Thus, the reaction may occur mostly in the solid and liquid phases ofreactants.

For example, sodium nitrite has the lowest boiling point (320° C.) ofthe reactants. Thus, in certain embodiments the temperature of theheating element 36 may be maintained between about 270° C. and 320° C.to melt the sodium nitrite while avoiding vaporizing it. Thus, a liquidreactant can move to contact solid reactants. By controlling thetemperature, the reaction may be controlled to allow the nitric oxide tobe released over a desired period of time, such as, for example, about30 minutes. Nevertheless, in other embodiments, the reactants may beheated to greater temperatures, such as between about 300° C. and 700°C. Thus, although the generator 10 may generate nitric oxide at lowertemperatures, its use is not limited to the lower temperatures.

Once the reaction is generating nitric oxide, the resulting nitric oxidegas may be mixed 56 with a diluent gas, such as nitrogen, air, or thelike, to dilute the nitric oxide to a therapeutically safe level, suchas between about 20 and about 500 ppm. A range of about 250 to about 400ppm is particularly useful, with a target of just over 300 ppm. Inselected embodiments, the diluent gas may be pumped into the vessel 12at a desired rate (e.g., 0.5 L/min) where it may mix with the nitricoxide and exit through an outlet 20. In other embodiments, the nitricoxide may be drawn into a stream of diluent gas using a principle suchas the venturi effect.

Referring to FIG. 5A, in selected embodiments, a nitric oxide generationsystem 60 may include a diluent gas source 62, a nitric oxide generator10, and a destination for diluted nitric oxide gas 64. In certainembodiments, the system 60 may utilize a feedback loop to control theconcentration of nitric oxide gas in the diluted nitric oxide gas 64.For example, one or more sensors 66 may be used to sense theconcentration of nitric oxide in the diluted nitric oxide gas 64. Thesesensors may provide a feedback signal 67 to various controls 68. Thesecontrols 68 may be used to adjust the temperature of a heating element36 of the nitric oxide generator 10. By adjusting the temperature, heat,current, or other energy control point, the speed of the reaction andthus the nitric oxide release rate may be adjusted to achieve a desiredconcentration of nitric oxide in the diluted gas 64.

Referring to FIG. 5B, in an alternative embodiment, a feedback signal 67may be used to control the flow rate of a diluent gas through the nitricoxide generator 10. This may also adjust the concentration of nitricoxide in the diluted gas 64. This may be accomplished, for example, byadjusting the speed of a pump moving the diluent gas. Alternatively, thefeedback signal may be used to control a valve to regulate the flow rateof diluent gases through the nitric oxide generator 10. In selectedembodiments, a system 60 may utilize both types of feedback illustratedin FIGS. 5A and 5B to control the concentration of nitric oxide in thestream or supply of diluted gas 64.

Referring to FIG. 6, one embodiment of a method 70 for making anitric-oxide-producing tablet 16 using a dry granulation process isillustrated. In certain embodiments, such a method 70 may includeinitially combining 72 various ingredients, such as active ingredients74 and excipients 76, to produce a tablet 16. In selected embodiments,active ingredients may include a non-deliquescent nitrite compound 78, anitrate compound 80, and a metal oxide 82. In one embodiment, the activeingredients may include about 33 percent by weight of sodium nitrite,about 17 percent by weight of potassium nitrate, and about 50 percent byweight of chromic oxide. A stoichiometric mixture may be used or anexcess of all ingredients except for a rate controlling reactant.

The tablet 16 may also include one or more excipients 76 that mayimprove the manufacturability of the tablet 16 as well as increase thethermal conductivity, heat transfer capacity, or temperature uniformity,and thus nitric oxide production, of the tablet 16. For example, thetablet 16 may include one or more binders 84, lubricants 86, andantiadherents 88. In one embodiment, a suitable binder 84 may includecalcium silicate (Ca₂SiO₄), a suitable lubricant 86 may include zincstearate, and a suitable antiadherent 88 may include talc to preventpunch sticking. The calcium silicate acts a compression aid to produce atablet 16 with acceptable hardness and friability. The calcium silicatedoes not replace the ferric oxide disclosed by Ray and Ogg. It serves adifferent function without harming nitric oxide production. In fact,ferric oxide was found to be detrimental to tablet 16 physicalproperties, producing tablets 16 with unacceptable brittleness andfriability.

In selected embodiments, combining 72 the ingredients may includeinitially combining all the active ingredients 74 with about half of theexcipients 76. These ingredients may then be blended 90 with a devicesuch as a V-blender. This mixture may then be pressed 92 using a tabletor other suitable press to create slugs containing the above-mentionedingredients. In selected embodiments, the slugs may be pressed to ahardness above about 5 kiloponds. In other embodiments, the slugs may bepressed to a hardness of between about 10 and 20 kiloponds. In otherembodiments, the slugs may be pressed to a hardness of about 14kiloponds.

The compressive force applied to the tablets 16 may be important and mayaffect the nitric oxide production of the tablets 16. In general, ahigher compressive force will improve the nitric oxide production of atablet 16. Higher compressive forces reduce air volume and improvechemical intimacy between the reactants, as well as increasing thethermal conductivity of the tablet 16 by both conforming particles toone another and removing pores or other voids in the tablet 16. Theimproved thermal conductivity provides better heat transfer to thereactants, and better molecular contact, thereby providing more uniformheating and better nitric oxide production.

Once created, the slugs may be milled 94, such as with a Fitzmill ModelDASO 6, to produce granules. These granules may be filtered through, forexample, about a number 20 mesh screen to remove larger particles. Thegranules, as well as the remaining binder 98, lubricant 100, andantiadherents 102 may then be combined 96 and returned to the blenderfor mixing. This mixture may then be returned to the tablet press tocreate 104 the tablets 16. In selected embodiments, a different tool ordie may be used to produce tablets 16 with an aperture in the middle, asillustrated in FIG. 3. In certain embodiments, the tablets 16 may bepressed to a final hardness above about 5 kiloponds. In otherembodiments, the tablets 16 may be pressed to a hardness of betweenabout 10 and 20 kiloponds. In other embodiments, the tablets 16 may bepressed to a hardness of about 17 kiloponds.

Tablets 16 made in accordance with a method 70 have been found to havegreatly improved physical properties. They also exhibit significantlyimproved nitric oxide production in the generator 10 disclosed byApplicants. That is, the tablets 16 greatly outperform the powders,“pellets,” or molded “cylindrical pieces” disclosed by Ray and Ogg whenheated in the nitric oxide generator 10. Because of the improvedperformance, significantly less amounts of active ingredients arerequired to produce a tablet 16 having acceptable nitric oxideproduction.

For example, a 5 gram tablet made in accordance with Ray and Ogg'smethod and containing approximately 85 percent by weight of activeingredients produced only 2.4 mL of nitric oxide gas when heated in thegenerator 10. By contrast, a five gram tablet 10 made in accordance witha method 70 and containing only 10 percent by weight of activeingredients produced about 11.5 mL of nitric oxide in the generator 10.This constitutes a more than 3000 percent increase in efficiency.

In selected embodiments, a tablet 16 made in accordance with the method70 and exhibiting vastly improved efficiency may include about 3.3percent by weight of sodium nitrite, about 1.7 percent by weight ofpotassium nitrate, about 5 percent by weight of chromic oxide, about 87percent by weight of calcium silicate, about 2 percent by weight of zincstearate, and about 1 percent by weight of talc. When compressed to ahardness of about 12.9 kiloponds, a 5 gram tablet 16 having the abovecomposition produced approximately 11.5 mL of nitric oxide and hadacceptable friability to create a satisfactory manufactured product.

Referring to FIG. 7, as mentioned, a tablet 16 in accordance with theinvention may be provided as a granulated structure that may actuallyincrease nitric oxide production. For example, as illustrated, reactantswithin the tablet 16 may be agglomerated into granulated subdomains 110within the tablet 16. The binder 112 (e.g., calcium silicate) may bepresent within and between the granules 110. Each of the subdomains 110may be compressed to a hardness of greater than 5 kiloponds and moreideally between about 10 and 20 kiloponds to create chemical intimacybetween the reactants of each granule. As was described in associationwith FIG. 6, this may be accomplished by creating slugs from a mixturecontaining the reactants and then milling the slugs to create granules110 of a desired size. These granules 110 may also improve theflowability of the mixture to prevent the mixture from stickingtogether, thereby enabling production of a tablet 16 with improvedphysical characteristics.

As mentioned, the calcium silicate binder is a material that acts as acompression aid when forming the tablet 16. An unexpected benefitprovided by the calcium silicate after compression is that it providesan effective path of thermal conduction to the reactants. This path ofthermal conduction is provided both intergranularly, by the binderincluded within each granule 110, as well as extra-granularly, by thebinder 112 provided between each granule 110. These paths of thermalconduction provide an effective mechanism to transfer heat to eachgranule 110 and to the reactants within each granule 110. This enablesheat to be more efficiently transported to the reactants, significantlyimproving nitric oxide production by getting more of the reactants toreact with one another. It follows that greater compressive forcesapplied to the tablet 16 may actually increase the chemical intimacybetween the reactants and the binder and thus improve nitric oxideproduction.

FIG. 8 is a graph showing the effect of compressive force on nitricoxide production. Each of the curves 120 a, 120 b represents the nitricoxide production of one 5-gram tablet 16 containing 10 percent by weightactive ingredients and made in accordance with the method 70 illustratedin FIG. 6. The tablets 16 were heated to about 500° C. in the nitricoxide generator 10 illustrated in FIGS. 2A and 2B with nitrogen gaspassing through the unit at a flow rate of about 0.5 L/min. The nitricoxide concentration was measured (in ppm) in the outgoing gas stream, asshown on the vertical axis of the graph.

Both tablets 16 represented by the curves 120 a, 120 b contain about 3.3percent by weight of sodium nitrite, about 1.7 percent by weight ofpotassium nitrate, about 5 percent by weight of chromic oxide, about 89percent by weight of calcium silicate, and about 1 percent by weight ofzinc stearate. The only significant difference between the tablets 16 isthat the tablet 16 represented by the curve 120 a was compressed to ahardness of about 16.0 kiloponds, whereas the tablet 16 represented bythe curve 120 b was compressed to a hardness of about 10.0 kiloponds.

As can be seen for both tablets 16, nitric oxide production is greatestat the beginning of production. This production diminishes over thetypical (e.g. about 30 to 90 minutes) 60 minute interval during whichthe reactants are consumed. As can also be observed, the tablet 16represented by the curve 120 a, which was compressed to a hardness ofabout 16.0 kiloponds, generated significantly more nitric oxide than thetablet 16 represented by the curve 120 b and compressed to a hardness ofabout 10.0 kiloponds. These results bolster the conclusion that greatercompressive forces applied to the tablet 16 increase the thermalconductivity, chemical intimacy, or both of the tablets 16 and thusimprove nitric oxide production. That is, greater compressive forcesachieve nitric oxide yields, in a stream of a breathing gas (e.g. air,nitrogen) having a volume of about half a liter per minute, closer tothe theoretical yield. These results also achieve a target yield of atleast 300 ppm of nitric oxide for at least 30 minutes.

The present invention may be embodied in other specific forms withoutdeparting from its basic features or essential characteristics. Thedescribed embodiments are to be considered in all respects only asillustrative, and not restrictive. The scope of the invention is,therefore, indicated by the appended claims, rather than by theforegoing description. All changes within the meaning and range ofequivalency of the claims are to be embraced within their scope.

1. A method of generating nitric oxide, the method comprising: providinga solid tablet comprising non-deliquescent reactants; heating the tabletto melt at least one of the reactants to promote reaction thereof,thereby generating nitric oxide; mixing the nitric oxide with a diluentgas to provide a therapeutically safe concentration of nitric oxide. 2.The method of claim 1, further comprising: providing a heat source;providing a vessel containing the heat source; and positioning thetablet within the vessel and in thermal communication with the heatsource to receive heat therefrom.
 3. The method of claim 2, wherein thetablet further comprises an inert binder providing a substantially solidpath of thermal conduction between granules of reactants.
 4. The methodof claim 2, wherein the tablet is compressed to a hardness providing athermal conductivity effective to heat the reactants substantiallyexclusively by thermal conduction.
 5. The method of claim 2, furthercomprising controlling the heat source to melt, yet avoid vaporizing, atleast one of the reactants.
 6. The method of claim 2, further comprisingcontrolling the heat source to melt at least one of the reactants, andto avoid vaporizing any of the reactants.
 7. The method of claim 2,wherein the hardness of the tablet is selected to be greater than 5kiloponds.
 8. The method of claim 2, wherein the hardness of the tabletis selected to be greater than 9 kiloponds.
 9. The method of claim 2,wherein the hardness of the tablet is selected to be from about 10kiloponds to about 20 kiloponds.
 10. The method of claim 2, wherein thereactants consist essentially of: a non-deliquescent nitrite compound; anitrate compound; and a single metal oxide.
 11. The method of claim 3,wherein the reactants comprise: a non-deliquescent nitrite compound; anitrate compound; and a metal oxide.
 12. The method of claim 11, whereinthe inert binder comprises calcium silicate.
 13. The method of claim 11,wherein the non-deliquescent nitrite compound comprises sodium nitrite.14. The method of claim 11, wherein the nitrate compound comprisespotassium nitrate and the metal oxide comprises chromic oxide.
 15. Themethod of claim 2, further comprising agglomerating the reactants intogranulated sub-domains within the tablet.
 16. The method of claim 2,further comprising selecting materials and processing to minimizefriability of the tablet.
 17. The method of claim 1, further comprising:providing a non-deliquescent nitrite compound as at least one of thereactants; providing a nitrate compound as at least one of thereactants; providing a metal oxide as at least one of the reactants;providing an inert binder; and providing a substantially solid path ofthermal conduction between the reactants by combining the reactants withthe inert binder to fill spaces between reactants with the inert binder.18. The method of claim 17, wherein the inert binder comprises calciumsilicate.
 19. The method of claim 17, wherein the non-deliquescentnitrite compound comprises sodium nitrite.
 20. The method of claim 17,wherein the nitrate compound comprises potassium nitrate and the metaloxide comprises chromic oxide.